Morphine, natural product

In the strict sense, opiates are drugs which are derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. In the wider sense, opiates are morphine-like drugs with non-peptidic structures. The old term opiates is now more and more replaced by the term opioids which applies to any substance, whether endogenous or synthetic, pqrtidic or non-peptidic, that produces morphine-like effects through an action on opioid receptors. 

Morphine is a natural product. Morphine was isolated as a pure compound from crude opium, an exudate of the poppy, in 1804. Morphine is quite a complicated molecule. 

The first group contains the natural products morphine, codeine and thebaine, which have been isolated from the natural product opium. In addition, the group contains various semi-synthetic derivatives of morphine, codeine and thebaine, which are prepared by chemical modifications of these natural products... 

In the 1970s, Hughes et al. were the first to show that two very different chemical structures have similar agonist properties (3). The opioid natural product, morphine (3), was found to resemble the N-terminal structure of the endogenous opioid peptides, enkephalins, (4a) and (4b), and j3-endorphin (5) (Fig. 15.2). The remarkable similarity between the morphine phenol system and the IV-terminal tyrosine residue in the peptide opioids implied that these units reacted with opioid receptors in a similar fashion to elicit comparable responses (4-6). 

As noted in the Chapter 6 A Deeper Look, more than half of all new drug candidates come either directly or indirectly from natural products. Morphine from the opium poppy, prostaglandin El from sheep prostate glands, erythromycin A from a Streptomyces erythreus bacterium cultured from a Philippine soil sample, and benzylpenicillin from the mold Penicillium notatum are examples. The immunosuppressive agent rapamycin, whose structure is shown on the previous page, was first isolated from a Streptomyces hygroscopicus bacterium found in a soil sample from Easter Island (Rapa Nui), located 2200 miles off the coast of Chile. 

Morphine is a complex natural product with potent analgesic properties... 

During the nineteenth century, chemists had a good deal of success in isolating and purifying natural products from plant sources. Morphine was isolated as a pure compound from crude opium in 1804. Quinine was isolated from the bark of the cinchona tree in 1820 and was initially employed as a fever reducer. However, its effectiveness against malaria was soon discovered and it found an alternative highly important medical use. Sodium salicylate was isolated from the bark of the willow tree in 1821 and was also shown to have analgesic, antipyretic, and antiinflammatory properties. It took an additional 76 years, until 1897, to synthesize the acetyl derivative, acetylsalicyclic acid, commonly known as aspirin. 

The use of natural products as medicine has invoked the isolation of active compounds the first commercial pure natural product introduced for therapeutic use is generally considered to be the narcotic morphine (1), marketed by Merck in 1826, and the first semi-synthetic pure dmg aspirin (2), based on a natural product salicin (3) isolated from Salix alba, was introduced by Bayer in 1899. This success subsequently led to the isolation of early dmgs such as cocaine, codeine, digitoxin (4), quinine (5), and pilocarpine (6), of which some are still in use. ... 

Classification based on physiological activity The interest in natural products is frequently initiated by attempts to isolate and clarify a physiologically active principle of plant or animal origin. Actually, many medicines currently in use are natural products, e.g. alkaloids, such as morphine and penicillin G. 

The above mentioned reactions are widely used in alkaloid modification. A good example of alkaloid modifications for clinical curation purposes are opioides. Morphine and codeine are natural products of Papaver somniferum. However, the codeine is naturally produced in small amounts. This is one reason why it is produced synthetically from morphine by modification. As codeine is the 3-0-methyl ether of morphine, the mono-O-methylation occurs in the acidic phenolic hydroxyl. Pholcodine is obtained by modification of morphine through alkylation with A-(chloroethyl)morpholine. Moreover, dihydrocodeine, hydro-morphone and heroine are also obtained from morphine through modifications. 

A variety of 2,4-oxazolidinedione moieties have been prepared as precursors to A-acyliminium ions. These, in turn, have been used in synthetic approaches to 13-aza-16-oxasteroids, interesting and novel heterocycles, " and natural products such as ( )-p-conhydrine, 294b, ( )-6>-methylpaUidinine, 297, 4-oxa-2-aza-podophyllotoxin, 299, and morphine, 302. Introduction of the 2,4-oxazolidinedione can be achieved by conventional alkylation. However, it is normally introduced through Mitsunobu chemistry using diisopropyl azodicar-boxylate or diethyl azodicarboxylate. " The former reagent is favored by... 

Marine natural products are also on trial as CNS aids (SNX-111, a peptide from mollusks, which is a nonaddictive analgesic agent 100-1,000 fold more potent than morphine, now in clinical phase III) and against pathogenic fimgi (15G256y, a macrolide from filamentous fimgi). 

The presence of this tricyclic system in both morphine and the steroids prompted a book by Louis Pieser, entitled Natural Products Related to Phenathrene. This tome, long since out of print, reviewed the chemistries of both these two classes. 

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